Drug resistance is an ever increasing problem in modern medicine impacting the treatment of conditions as diverse as bacterial infections, viral infections, protozoan infections, fungal infections, and cancer.
In particular, the worldwide emergence of antibiotic-resistant bacteria threatens to undo the dramatic advances in human health that followed the discovery of these drugs. Antibiotic drug resistance is especially acute with tuberculosis, which infects one-third of all humans, most of whom live in the developing world. The health care establishment is countering this challenge by trying to create new antibiotics and by limiting the use of those already available. However, this approach has not yet produced the desired effect, as the prevalence of resistant strains continues to increase.
Drug resistance is also a problem with viruses, including the human immunodeficiency virus (“HIV”). In fact, HIV drug resistance is rapidly becoming an epidemic. One study of HIV infected patients between 1996 and 1999, shows that about 78% of patients harbored viruses that were resistant to at least one class of drugs, 51% had viruses that were resistant to two classes of drugs, and 18% had viruses that were resistant to three classes of drugs. Thus, HIV drug therapies must constantly evolve to keep pace with the evolution of resistance.
Drug resistance is also a problem during cancer therapy. It is estimated that half of all cancer patients are cured, mostly by a combination of surgery, radiotherapy and/or chemotherapy. However, some cancers can only be treated by chemotherapy, and in those cases, only one in five patients survives long-term. It is believed that the overriding reason for this poor result is drug resistance, wherein the tumors are either innately resistant to the drugs available, or else are initially sensitive but evolve resistance during treatment and eventually re-grow. Allen J D, et al. Cancer Research (2002) 62, 2294-2299.
Drug resistance also occurs with protozoa such as Plasmodium spp., the genus of protozoa responsible for malaria. In recent years, drug resistance has become one of the most important problems in malaria control. Resistance in vivo has been reported to all anti-malaria drugs except artemisinin and its derivatives. This necessitates the use of drugs which are more expensive and may have dangerous side effects.
Thus, there is a great need for compounds that inhibit the mutations that confer drug resistance and methods for using such compounds to treat and prevent drug resistant conditions.